EP0094513B1 - Sustained-release body containing an active ingredient - Google Patents

Sustained-release body containing an active ingredient Download PDF

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Publication number
EP0094513B1
EP0094513B1 EP83103763A EP83103763A EP0094513B1 EP 0094513 B1 EP0094513 B1 EP 0094513B1 EP 83103763 A EP83103763 A EP 83103763A EP 83103763 A EP83103763 A EP 83103763A EP 0094513 B1 EP0094513 B1 EP 0094513B1
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EP
European Patent Office
Prior art keywords
polymer
active
substance
degradable
microporous
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EP83103763A
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German (de)
French (fr)
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EP0094513A2 (en
EP0094513A3 (en
Inventor
Wolfgang Dr. Dipl.-Chem. Lange
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Akzo Patente Te Wuppertal Bondsrepubliek Dui GmbH
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Akzo GmbH
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
    • C05G5/00—Fertilisers characterised by their form
    • C05G5/40—Fertilisers incorporated into a matrix

Definitions

  • the invention relates to active ingredients such as pharmaceuticals, pesticides, peptides, hormones, enzymes and. Like. Containing bodies, which are able to release the active ingredient in a controlled manner to their environment over a long period of time.
  • the invention further relates to a method for producing such bodies.
  • the active ingredients have so far mostly been administered orally as a tablet, liquid, dispersion or as an injection, so that the medication is then present in the body in a relatively high concentration rather quickly and the concentration is reduced over time.
  • the therapeutically reasonable concentration level is only set for a short time. Initially, the level may be too high, which creates the risk of an overdose, later on the level will be too low for a long time, and the level will continue to decrease.
  • Fertilizers e.g. B. are mostly in the form of a powder, for. B. brought ammonium phosphate into the field, which initially gives a high concentration of the fertilizer. With the first rain, however, a considerable amount of the salt is swept away or seeps away in the soil, so that the concentration in the soil becomes poor and the plant has much less of the active ingredient required.
  • microcapsules in which the active substance is surrounded by a membrane through which the active substance can diffuse, have become established particularly in pharmacy.
  • a disadvantage of the microcapsules is that the desired thickness distribution of the wall thickness is difficult to achieve for a desired delivery rate. Often, the capsules are not completely sealed, little stress, which can lead to uncontrolled drug release.
  • the object of the invention is therefore to provide a method with which such bodies can be produced in a simple and economical manner.
  • Another object of the invention is to produce active ingredient-containing polymers which serve as a matrix for the active ingredient and are themselves degradable.
  • Another object of the invention is to provide a system which can ensure constant delivery rates, i. H. according to a zero order speed law, and which can also be loaded with different active substances at the same time in different concentrations.
  • a process for producing an active substance-containing body for the long-term release of active substances which is characterized in that a powdered or granular microporous polymer (A) is loaded with active substance and the polymer containing the active substance in a matrix of degradable polymer (B) distributed.
  • the microporous, active ingredient-containing polymer (A) is preferably distributed in a melt of a degradable polymer (B), the melting point of which is below the melting temperature of the microporous polymer (A). The melt is then cooled.
  • Poly (B) in particular is a degradable polymer Suitable are those that are biodegradable in the human or animal body.
  • the degradable copolymers of lactic acid are particularly suitable for this.
  • microporous polymer (A) it is expedient if a likewise degradable polymer is used as the microporous polymer (A). In many cases it is favorable if the microporous polymer (A) has a rate of degradation which is lower than the rate of degradation of the matrix polymer (B).
  • a plasticized polymer is used as the polymer (B).
  • customary plasticizers can be used, which of course must be appropriate for the intended use of the body containing the active ingredient.
  • no toxic or harmful plasticizers may be used for applications in the human or animal body.
  • plasticized polymer (A) instead of a polymer (B) different from (A). Also, in many (B) itself, if it holds plasticizers, it may have a higher melting point than (A).
  • the distribution of the polymer (A) loaded with active ingredient in polymer (B) can, for. B. by simply stirring into a melt of (B) or by kneading (A) and (B) or by extruding them together.
  • the production of moldings is very simple.
  • the invention further relates to an active substance-containing body for the long-term release of active substances, which is characterized by a matrix of degradable polymer (B) in which microporous powdered or granular polymers (A) loaded with active substance are uniformly distributed.
  • the polymer (A) is preferably also a degradable polymer whose rate of degradation is slower than the rate of degradation of the matrix polymer (B).
  • the degradable polymer (B) is preferably a copolymer of lactic acid.
  • a particular advantage of the invention is that it makes it possible to store both solid and liquid active substances in amounts not previously achieved in the body intended for the active substance release and for a long time, which can last from several months to six months and beyond to deliver in a controlled manner.
  • Another advantage of the invention is that it allows a single body to be used to deliver a large number of active ingredients, which can be coordinated in their relative concentrations, in a controlled manner. It is thus possible to put together commonly used preparation combinations without any problems by separately introducing each pharmaceutical, whether or not mixed, into powder (A), mixing the differently loaded powders (A) together in the desired amount and in the matrix (B) distributed.
  • Suitable polymers within the scope of the invention are, in particular, polylactides based on dl-lactic acid, polymers of I (+) - lactic acid, d (-) - lactic acid and the copolymers which can be prepared from the lactic acids mentioned here.
  • Suitable comonomers are glycolide, caprolactam and ⁇ -propiolactone.
  • the copolymer consisting of 75% (wt) L (+) lactide and 25% glycolide, was first prepared by block polymerization with 0, 03 wt .-% tin octoate and 0.01 wt .-% lauryl alcohol as a catalyst (Polymer 1979, Vol. 20, p 1459).
  • Microporous polylactide was initially produced as a carrier for the active ingredient.
  • 90.3 g of d (-) - polylactide with a molecular weight of approximately 40,000 were dissolved in 400 ml of xylene and then allowed to cool without stirring.
  • the resulting homogeneous mass was suction filtered and then vacuum dried at 60 ° C. Hg intrusion measurements on this powder showed a value of 55% pore volume.
  • the molded article obtained had a degree of loading with cetyl alcohol of 20%, based on the total weight.

Description

Die Erfindung betrifft Wirkstoffe wie Pharmazeutika, Pestizide, Peptide, Hormone, Enzyme u. dgl. enthaltende Körper, welche in der Lage sind, den Wirkstoff kontrolliert über lange Zeit an ihre Umgebung abzugeben.The invention relates to active ingredients such as pharmaceuticals, pesticides, peptides, hormones, enzymes and. Like. Containing bodies, which are able to release the active ingredient in a controlled manner to their environment over a long period of time.

Die Erfindung betrifft ferner ein Verfahren zur Herstellung derartiger Körper.The invention further relates to a method for producing such bodies.

Man hat sich seit langem bemüht, Wirkstoffe, wie Arzneimittel, Hormone, Düngemittel, Schädlingsbekämpfungsmittel, Spurenelemente, Duftstoffe u. dgl. kontrolliert über längere Zeiträume abzugeben.There has been a long effort to find active ingredients such as drugs, hormones, fertilizers, pesticides, trace elements, fragrances and the like. The like. To deliver controlled over longer periods.

Bei der pharmazeutischen Anwendung werden die Wirkstoffe bis jetzt meistens oral als Tablette, Flüssigkeit, Dispersion oder als Injektion verabreicht, so daß das Medikament dann ziemlich schnell im Körper in einer hohen Konzentration vorliegt und die Konzentration im Laufe der Zeit abgebaut wird.In pharmaceutical use, the active ingredients have so far mostly been administered orally as a tablet, liquid, dispersion or as an injection, so that the medication is then present in the body in a relatively high concentration rather quickly and the concentration is reduced over time.

Da die Wirkstoffabnahme fast immer exponentiell erfolgt, ist leicht einzusehen, daß bei dieser Art von Wirkstoffgabe das therapeutisch sinnvolle Konzentrationsniveau nur kurzfristig eingestellt wird. Anfänglich kann ein zu hohes Niveau gegeben sein, was die Gefahr einer Überdosis mit sich bringt, später liegt dann über lange Zeit ein zu niedriges, ständig noch abnehmendes Niveau vor.Since the decrease in active ingredient is almost always exponential, it is easy to see that with this type of active ingredient the therapeutically reasonable concentration level is only set for a short time. Initially, the level may be too high, which creates the risk of an overdose, later on the level will be too low for a long time, and the level will continue to decrease.

Für viele Anwendungsgebiete sind jedoch über einen längeren Zeitraum konstante Wirkstoffkonzentrationen erwünscht.However, constant drug concentrations over a longer period of time are desired for many areas of application.

Analoge Verhältnisse sind auch auf Gebieten wie der Landwirtschaft und der Forstwirtschaft beispielsweise gegeben. Düngemittel z. B. werden meistens in Form eines Pulvers z. B. Ammoniumphosphat auf den Acker gebracht, wodurch zunächst eine hohe Konzentration des Düngemittels gegeben ist. Bei dem ersten Regen wird jedoch eine beachtliche Menge des Salzes weggeschwemmt bzw. versickert im Boden, so daß die Konzentration im Boden verarmt und der Pflanze wesentlich weniger des benötigten Wirkstoffs zur Verfügung steht.Analogous relationships also exist in areas such as agriculture and forestry. Fertilizers e.g. B. are mostly in the form of a powder, for. B. brought ammonium phosphate into the field, which initially gives a high concentration of the fertilizer. With the first rain, however, a considerable amount of the salt is swept away or seeps away in the soil, so that the concentration in the soil becomes poor and the plant has much less of the active ingredient required.

Man hat sich bemüht, diese Nachteile zu beheben, indem man die Wirkstoffe in einem Depot unterbringt, z. B. in mikroporösen Pulvern, aus denen der Wirkstoff verlangsamt abgegeben werden soll.Efforts have been made to remedy these disadvantages by placing the active ingredients in a depot, e.g. B. in microporous powders from which the active ingredient is to be released slowly.

Besonders in der Pharmazie haben sich sogenannte Mikrokapseln eingebürgert, bei denen der Wirkstoff von einer Membran umgeben ist, durch die der Wirkstoff durchdiffundieren kann. Von Nachteil bei den Mikrokapseln ist, daß die gewünschte Dickenverteilung der Wandstärke für eine erstrebte Abgaberate schwierig zu erreichen ist. Oft sind die Kapseln nicht ganz dicht, wenig beanspruchbar, was zu unkontrollierter Wirkstoffabgabe führen kann.So-called microcapsules, in which the active substance is surrounded by a membrane through which the active substance can diffuse, have become established particularly in pharmacy. A disadvantage of the microcapsules is that the desired thickness distribution of the wall thickness is difficult to achieve for a desired delivery rate. Often, the capsules are not completely sealed, little stress, which can lead to uncontrolled drug release.

Man hat ferner versucht, den Wirkstoff in einer Matrix zu dispergieren, aus welcher der Wirkstoff durch Diffusion heraustreten kann. Nachteilig bei diesem Vorgehen ist, daß eine allmähliche Abnahme der Wirkstoffabgabe eintritt. Es ist also mit diesem Verfahren nicht möglich, über längere Zeit eine konstantbleibende Abgabe zu erreichen.Attempts have also been made to disperse the active ingredient in a matrix from which the active ingredient can emerge by diffusion. The disadvantage of this procedure is that there is a gradual decrease in the release of active substance. It is therefore not possible with this method to achieve a constant delivery over a long period of time.

In der US-PS 3 887 699 und der US-PS 4 011 312 wird ein ähnliches Prinzip der Langzeitabgabe von Wirkstoffen beschrieben. Dort wird die Lehre vermittelt, einen Wirkstoff in einem polymeren Material zu dispergieren, das biskompatibel ist und aus dem der Wirkstoff an die Oberfläche diffundiert.A similar principle of long-term release of active substances is described in US Pat. No. 3,887,699 and US Pat. No. 4,011,312. There the teaching is taught to disperse an active ingredient in a polymeric material that is bis-compatible and from which the active ingredient diffuses to the surface.

Von Nachteil bei diesen Verfahren ist, daß man in der Matrix nur bestimmte Höchstmengen des Wirkstoffs verteilen kann, da sonst die Handhabung des Materials schwierig wird und zudem der Wirkstoff leicht, bevor es zur Anwendung kommt, bereits aus dem Polymer herausschwitzen kann.The disadvantage of these processes is that only certain maximum amounts of the active ingredient can be distributed in the matrix, since otherwise the material becomes difficult to handle and, moreover, the active ingredient can easily sweat out of the polymer before it is used.

Es besteht deshalb noch ein Bedürfnis nach verbesserten Körpern, welche Wirkstoffe enthalten und diese auf kontrollierte Weise über lange Zeit hinaus an ihre Umgebung abgeben können.There is therefore still a need for improved bodies which contain active ingredients and can release them into their environment in a controlled manner over a long period of time.

Aufgabe der Erfindung ist es deshalb, ein Verfahren zur Verfügung zu stellen, mit dem sich solche Körper auf einfache und wirtschaftliche Weise herstellen lassen.The object of the invention is therefore to provide a method with which such bodies can be produced in a simple and economical manner.

Aufgabe der Erfindung ist es ferner, wirkstoffenthaltende Polymere herzustellen, die als Matrix für den Wirkstoff dienen und selbst abbaubar sind.Another object of the invention is to produce active ingredient-containing polymers which serve as a matrix for the active ingredient and are themselves degradable.

Aufgabe der Erfindung ist es ferner, ein derartiges Wirkstoff/Polymersystem zur Verfügung zu stellen, in dem die Menge des eingelagerten Wirkstoffs in weiten Grenzen variiert werden kann, so daß die Intensität der konstanten Wirkstoffabgabe gut und reproduzierbar einstellbar ist.It is also an object of the invention to provide such an active ingredient / polymer system in which the amount of active ingredient incorporated can be varied within wide limits, so that the intensity of the constant release of active ingredient can be adjusted well and reproducibly.

Aufgabe der Erfindung ist es ferner, ein Polymer/Wirkstoffsystem zur Verfügung zu stellen, das vielseitig einsatzfähig ist, auch in physiologischen Systemen, in denen biokompatible Polymere erforderlich sind.It is also an object of the invention to provide a polymer / active substance system which can be used in a variety of ways, even in physiological systems in which biocompatible polymers are required.

Aufgabe der Erfindung ist es außerdem, ein System zur Verfügung zu stellen, das konstante Abgaberaten gewährleisten kann, d. h. nach einem Geschwindigkeitsgesetz nullter Ordnung, und das außerdem mit verschiedenen Wirkstoffen gleichzeitig ggf. jeweils in verschiedenen Konzentrationen beladen werden kann.Another object of the invention is to provide a system which can ensure constant delivery rates, i. H. according to a zero order speed law, and which can also be loaded with different active substances at the same time in different concentrations.

Diese Aufgabe wird durch ein Verfahren zur Herstellung eines wirkstoffenthaltenden Körpers für die Langzeitabgabe von Wirkstoffen gelöst, das dadurch gekennzeichnet ist, daß man ein pulver- oder granulatförmiges mikroporöses Polymer (A) mit Wirkstoff belädt und das den Wirkstoff enthaltende Polymer in einer Matrix aus abbaubarem Polymer (B) verteilt. Vorzugsweise wird die Verteilung des mikroporösen, Wirkstoff enthaltenden Polymers (A) in einer Schmelze eines abbaubaren Polymers (B) vorgenommen, dessen Schmelzpunkt unterhalb der Schmelztemperatur des mikroporösen Polymers (A) liegt. Anschließend wird die Schmelze abgekühlt. Als abbaubares Polymer (B) sind insbesondere Polymere geeignet, die im menschlichen oder tierischen Körper biologisch abbaubar sind. Hierzu sind vor allem die abbaubaren Copolymere der Milchsäure geeignet. Es ist zweckmäßig, wenn man als mikroporöses Polymer (A) ein ebenfalls abbaubares Polymer verwendet. Vielfach ist es günstig, wenn das mikroporöse Polymer (A) eine Abbaugeschwindigkeit aufweist, die niedriger ist als die Abbaugeschwindigkeit des Matrixpolymers (B).This object is achieved by a process for producing an active substance-containing body for the long-term release of active substances, which is characterized in that a powdered or granular microporous polymer (A) is loaded with active substance and the polymer containing the active substance in a matrix of degradable polymer (B) distributed. The microporous, active ingredient-containing polymer (A) is preferably distributed in a melt of a degradable polymer (B), the melting point of which is below the melting temperature of the microporous polymer (A). The melt is then cooled. Poly (B) in particular is a degradable polymer Suitable are those that are biodegradable in the human or animal body. The degradable copolymers of lactic acid are particularly suitable for this. It is expedient if a likewise degradable polymer is used as the microporous polymer (A). In many cases it is favorable if the microporous polymer (A) has a rate of degradation which is lower than the rate of degradation of the matrix polymer (B).

In einer besonderen Ausführungsform wird als Polymer (B) ein weichgemachtes Polymer verwendet. Dazu können übliche Weichmacher eingesetzt werden, die selbstverständlich dem vorgesehenen Verwendungszweck des den Wirkstoff enthaltenden Körpers angemessen sein müssen. So dürfen für Anwendungen im menschlichen oder tierischen Körper keine giftigen oder schädlichen Weichmacher eingesetzt werden.In a particular embodiment, a plasticized polymer is used as the polymer (B). For this purpose, customary plasticizers can be used, which of course must be appropriate for the intended use of the body containing the active ingredient. For example, no toxic or harmful plasticizers may be used for applications in the human or animal body.

Bei Einsatz eines Weichmachers ist es auch gut möglich, anstelle eines von (A) unterschiedlichen Polymers (B) weichgemachtes Polymer (A) zu verwenden. Auch kann in vielen (B) selbst, wenn es Weichmacher hält, an sich einen höheren Schmelzpunkt als (A) aufweisen.If a plasticizer is used, it is also possible to use plasticized polymer (A) instead of a polymer (B) different from (A). Also, in many (B) itself, if it holds plasticizers, it may have a higher melting point than (A).

Die Verteilung des mit Wirkstoff beladenen Polymers (A) in Polymer (B) kann z. B. durch einfaches Einrühren in eine Schmelze von (B) oder durch Verkneten von (A) und (B) oder durch gemeinsames Extrudieren geschehen. Die Herstellung von Formkörpern ist sehr einfach.The distribution of the polymer (A) loaded with active ingredient in polymer (B) can, for. B. by simply stirring into a melt of (B) or by kneading (A) and (B) or by extruding them together. The production of moldings is very simple.

Gegenstand der Erfindung ist ferner ein Wirkstoff enthaltender Körper für die Langzeitabgabe von Wirkstoffen, der gekennzeichnet ist durch eine Matrix aus abbaubarem Polymer (B), in der mit Wirkstoff beladene mikroporöse pulver- oder granulatförmige Polymere (A) gleichmäßig verteilt sind. Vorzugsweise handelt es sich bei dem Polymer (A) um ein ebenfalls abbaubares Polymer, dessen Abbaugeschwindigkeit geringer ist als die Abbaugeschwindigkeit des Matrixpolymeren (B). Vorzugsweise ist das abbaubare Polymere (B) ein Copolymer der Milchsäure.The invention further relates to an active substance-containing body for the long-term release of active substances, which is characterized by a matrix of degradable polymer (B) in which microporous powdered or granular polymers (A) loaded with active substance are uniformly distributed. The polymer (A) is preferably also a degradable polymer whose rate of degradation is slower than the rate of degradation of the matrix polymer (B). The degradable polymer (B) is preferably a copolymer of lactic acid.

Ein besonderer Vorteil der Erfindung ist, daß sie ermöglicht, sowohl feste als auch flüssige Wirkstoffe in bisher nicht erreichten Mengen in dem für die Wirkstoffabgabe bestimmten Körper zu speichern und über lange Zeit hinaus, die mehrere Monate bis zu einem halben Jahr und darüber hinaus dauern kann, kontrolliert abzugeben. Ein weiterer Vorteil der Erfindung ist, daß sie erlaubt, mit nur einem Körper eine Vielzahl von Wirkstoffen, die in ihren relativen Konzentrationen aufeinander abgestimmt sein können, kontrolliert abzugeben. So kann man üblicherweise verwendete Präparatekombinationen problemlos zusammenstellen, indem man jedes Pharmakon für sich, ggf. auch gemischt, jeweils separat in Pulver (A) einbringt, die so unterschiedlich beladenen Pulver (A) in der gewünschten Mengenkonstellation zusammenmischt und in der Matrix (B) verteilt.A particular advantage of the invention is that it makes it possible to store both solid and liquid active substances in amounts not previously achieved in the body intended for the active substance release and for a long time, which can last from several months to six months and beyond to deliver in a controlled manner. Another advantage of the invention is that it allows a single body to be used to deliver a large number of active ingredients, which can be coordinated in their relative concentrations, in a controlled manner. It is thus possible to put together commonly used preparation combinations without any problems by separately introducing each pharmaceutical, whether or not mixed, into powder (A), mixing the differently loaded powders (A) together in the desired amount and in the matrix (B) distributed.

Als Polymere im Rahmen der Erfindung kommen insbesondere infrage Polylactide auf der Basis von dl-Milchsäure, Polymere der I(+)-Milchsäure, der d(-)-Milchsäure und der aus den hier erwähnten Milchsäuren herstellbaren Copolymeren.Suitable polymers within the scope of the invention are, in particular, polylactides based on dl-lactic acid, polymers of I (+) - lactic acid, d (-) - lactic acid and the copolymers which can be prepared from the lactic acids mentioned here.

Ferner ist es möglich eine oder mehrere der genannten Milchsäuren zusammen mit Cokomponenten zu polymerisieren. Als brauchbare Comonomere seien genannt Glycolid, Caprolactam, β-Propiolacton.It is also possible to polymerize one or more of the lactic acids mentioned together with co-components. Suitable comonomers are glycolide, caprolactam and β-propiolactone.

Die Erfindung wird durch folgendes Beispiel näher erläutert :The invention is illustrated by the following example:

Beispiel 1example 1

Zum Aufbau einer zylindrischen Releaseeinheit von 20 mm Länge und 2 mm Durchmesser mit einer geplanten Lebensdauer von ca. 6 Monaten wurde zunächst das Copolymer, bestehend aus 75 % (Gew) L(+)-Lactid und 25 % Glykolid, durch Blockpolymerisation mit 0,03 Gew.-% Zinnoctoat und 0,01 Gew.-% Laurylalkohol als Katalysator (Polymer 1979, Vol. 20, S. 1459) hergestellt.To build a cylindrical release unit with a length of 20 mm and a diameter of 2 mm with a planned lifespan of approx. 6 months, the copolymer, consisting of 75% (wt) L (+) lactide and 25% glycolide, was first prepared by block polymerization with 0, 03 wt .-% tin octoate and 0.01 wt .-% lauryl alcohol as a catalyst (Polymer 1979, Vol. 20, p 1459).

Dazu wurden im Einzelnen 7,5 g L(+)-Dilactid zusammen mit 2,5 g Glykolid, (hergestellt nach Polymer 1979, Vol. 20, S. 1459) 2 h lang auf 200 °C im Bombenrohr erhitzt. Nach erfolgter Reaktion wurde der Inhalt abgekühlt, das Bombenrohr geöffnet und der Inhalt nach Aufschmelzen ausgegossen. Eine mit dem Copolymer durchgeführte Schmelzpunktbestimmung ergab einen Wert von 58 °C, der mit Literaturangaben (Polymer 1979, Vol. 20, S. 1463) übereinstimmt.For this purpose, 7.5 g of L (+) - dilactide together with 2.5 g of glycolide (manufactured according to Polymer 1979, Vol. 20, p. 1459) were heated to 200 ° C. in a bomb tube for 2 hours. After the reaction, the contents were cooled, the bomb tube opened and the contents poured out after melting. A melting point determination carried out with the copolymer gave a value of 58 ° C., which corresponds to the literature (Polymer 1979, Vol. 20, p. 1463).

Als Träger für den Wirkstoff wurde zunächst mikroporöses Polylactid hergestellt. Zu diesem Zweck wurden 90,3 g d(-)-Polylactid mit einem Molekulargewicht von ca. 40 000 in 400 ml Xylol gelöst und anschließend ohne Rühren abkühlen gelassen. Die dabei erhaltene, homogen erscheinende Masse wurde abgenutscht und anschließend bei 60 °C vakuumgetrocknet. Hg-Intrusionsmessungen an diesem Pulver ergaben einen Wert von 55 % Porenvolumen.Microporous polylactide was initially produced as a carrier for the active ingredient. For this purpose, 90.3 g of d (-) - polylactide with a molecular weight of approximately 40,000 were dissolved in 400 ml of xylene and then allowed to cool without stirring. The resulting homogeneous mass was suction filtered and then vacuum dried at 60 ° C. Hg intrusion measurements on this powder showed a value of 55% pore volume.

Daraufhin wurden 10 g des mikroporösen Polylactid-Pulvers mittels Vakuum bei Zimmertemperatur mit 100 ml 50 %iger, äthanolischer Lösung von Cetyl-Alkohol als Testsubstanz beladen. Nach vorsichtigem Abnutschen der überschüssigen Flüssigkeit wurde das alkoholfeuchte Pulver bei Zimmertemperatur im Vakuum getrocknet. Gravimetrische Untersuchung des getrockneten Pulvers ergab einen Beladungsgrad des Pulvers von etwa 58 %.Thereupon 10 g of the microporous polylactide powder were loaded with 100 ml of 50% ethanolic solution of cetyl alcohol as test substance by means of vacuum at room temperature. After the excess liquid had been carefully filtered off, the alcohol-moist powder was dried in vacuo at room temperature. Gravimetric examination of the dried powder showed a degree of loading of the powder of about 58%.

Zur Herstellung des erfindungsgemäßen Releasekörpers wurden dann 10 g des Cetylalkoholbeladenen Polylactidpulvers zusammen mit 19 g des Copolymeren bei ca. 55 °C solange verknetet, bis die Gesamtmasse homogen erschien. Anschließend wurde das erhaltene Produkt mittels Laborextrusiometer bei 55 °C zu einer Nudel von 2 mm Durchmesser extrudiert.To produce the release body according to the invention, 10 g of the polylactide powder loaded with cetyl alcohol were then kneaded together with 19 g of the copolymer at about 55 ° C. until the total mass appeared homogeneous. The product obtained was then extruded at 55 ° C. into a 2 mm diameter noodle using a laboratory extruderometer.

Der erhaltene Formkörper hatte einen Beladungsgrad mit Cetyl-Alkohol von 20 %, bezogen auf das Gesamtgewicht.The molded article obtained had a degree of loading with cetyl alcohol of 20%, based on the total weight.

Claims (12)

1. A process for the production of a body containing active substance for the sustained release of active substances, characterized in that a powder-form or granulate-form microporous polymer (A) is charged with active substance and the active-substance-containing polymer is dispersed in a matrix of degradable polymer (B).
2. A process as claimed in Claim 1, characterized in that the microporous, active-substance-containing polymer (A) is dispersed in a melt of a degradable polymer (B) of which the melting point is below the melting temperature of the microporous polymer (A) and the melt is cooled.
3. A process as claimed in Claims 1 and 2, characterized in that polymers which are biologically degradable in the human or animal body are used as the degradable polymer (B).
4. A process as claimed in Claims 1 to 3, characterized in that copolymers of lactic acid are used as the degradable polymer (B).
5. A process as claimed in Claims 1 to 4, characterized in that a degradable polymer is also used as the microporous polymer (A).
6. A process as claimed in Claim 5, characterized in that the microporous polymer (A) used is a polymer of which the degradation rate is lower than the degradation rate of the matrix polymer (B).
7. A process as claimed in Claims 1 to 6, characterized in that a plasticized polymer is used as the polymer (B).
8. A process as claimed in Claim 7, characterized in that plasticized polymer (A) is used as the polymer (B).
9. An active-substance-containing body for the sustained release of active substances, characterized by a matrix of degradable polymers (B) in which microporous powder-form or granulate-form polymers (A) charged with active substance are uniformly dispersed.
10. An active-substance-containing body as claimed in Claim 9, characterized by a similarly degradable polymer (A) of which the degradation rate is lower than the degradation rate of the matrix polymer (B).
11. An active-substance-containing body as claimed in Claims 9 and 10, characterized by copolymers of lactic acid as the degradable polymer (B).
12. An active-substance-containing body as claimed in Claims 9 to 11, characterized in that it contains various active substances or combinations of active substances.
EP83103763A 1982-05-14 1983-04-19 Sustained-release body containing an active ingredient Expired EP0094513B1 (en)

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DE3218150 1982-05-14

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EP0094513A2 (en) 1983-11-23
JPS58208212A (en) 1983-12-03
EP0094513A3 (en) 1984-08-22
DE3218150C2 (en) 1986-09-25
DE3218150A1 (en) 1983-11-17

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